Argininosuccinate synthetase 1 contributes to gastric cancer invasion and progression by modulating autophagy

• Published in: The FASEB journal 2018-05, Vol.32 (5), p.2601-2614
• Main Authors: Tsai, Chung‐Ying, Chi, Hsiang‐Cheng, Chi, Lang‐Ming, Yang, Huang‐Yu, Tsai, Ming‐Ming, Lee, Kam‐Fai, Huang, Hsiang‐Wei, Chou, Li‐Fang, Cheng, Ann‐Joy, Yang, Chih‐Wei, Wang, Chia‐Siu, Lin, Kwang‐Huei
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Argininosuccinate Synthase - biosynthesis; Argininosuccinate Synthase - genetics; autolysosome; Autophagy; Cell Line, Tumor; Disease-Free Survival; Female; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; iTRAQ; Male; Middle Aged; Neoplasm Invasiveness; Neoplasm Metastasis; pMTOR; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction; Stomach Neoplasms - drug therapy; Stomach Neoplasms - enzymology; Stomach Neoplasms - mortality; Stomach Neoplasms - pathology; Survival Rate; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.201700094r

Argininosuccinate synthetase 1 (ASS1) is a rate‐limited enzyme in arginine biosynthesis. The oncogenic potential of ASS1 in terms of prognosis and cancer metastasis in arginine prototrophic gastric cancer (GC) remains unclear at present. We identify differentially expressed proteins in microdissected GC tumor cells relative to adjacent nontumor epithelia by isobaric mass tag for relative and absolute quantitation proteomics analysis. GC cells with stable expression or depletion of ASS1 were further analyzed to identify downstream molecules. We investigated their effects on chemoresistance and cell invasion in the presence or absence of arginine. ASS1 was highly expressed in GC and positively correlated with GC aggressiveness and poor outcome. Depletion of ASS1 led to inhibition of tumor growth and decreased cell invasion via induction of autophagy‐lysosome machinery, resulting in degradation of active β‐catenin, Snail, and Twist. Ectopic expression of ASS1 in GC cells reversed these effects and protected cancer cells from chemotherapy drug‐induced apoptosis via activation of the AKT–mammalian target of rapamycin signaling pathway. ASS1 contributes to GC progression by enhancing aggressive potential resulting from active β‐catenin, Snail, and Twist accumulation. Our results propose that ASS1 might contribute to GC metastasis and support its utility as a prognostic predictor of GC—Tsai, C.‐Y., Chi, H.‐C, Chi, L.‐M., Yang, H.‐Y., Tsai, M.‐M., Lee, K.‐F., Huang, H.‐W., Chou, L.‐F., Cheng, A.‐J., Yang, C.‐W., Wang, C.‐S., Lin, K.‐H. Argininosuccinate synthetase 1 contributes to gastric cancer invasion and progression by modulating autophagy. FASEB J. 32, 2601–2614 (2018). www.fasebj.org